Project Summary - Ventricular arrhythmias remain the single most important cause of sudden cardiac death (SCO) among adults living in industrialized nations. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility as models for understanding more common causes of SCO. The best studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS). The observation that not all mutation carriers have equal risk for experiencing the clinical manifestations of LQTS (i.e., syncope, sudden death) has motivated the hypothesis that genetic factors other than the primary disease-associated mutation can modify the risk for disease- related morbidity and mortality. This proposal is the first competing renewal of R01-HL68880 which has funded a multi-national translational research collaboration to identify and characterize clinical predictors and candidate genetic modifiers in a large, unique LQTS founder population in South Africa (SA-LQTS). We have hypothesized the existence of two types of modifier genes: genes which affect myocardial repolarization and produce an arrhythmia-prone substrate, and genes which affect the propensity for triggering events acting through the autonomic nervous system. Specific Aim 1 describes our ongoing efforts to collect detailed information regarding the phenotype of the SA-LQTS population. We plan to continue our current focus on major clinical outcomes but will also explore more deeply for intermediate phenotypes related to abnormal myocardial repolarization and autonomic tone. For independent testing of candidate modifier gene hypotheses, we will also use a second large LQTS founder population ascertained in Finland (Fin-LQTS;80 families, >600 mutation carriers) that is associated with a different KCNQ1 mutation. The addition of this second LQTS founder population coupled with an important new collaboration with genetic epidemiologists at Columbia University will ensure that our observations are valid and have broad implications. In Specific Aim 2, we will examine the molecular mechanisms responsible for genetic and autonomic influences on the major repolarizing myocardial ionic currents. Finally, in Specific Aim 3 we will study genetic and epigenetic mechanisms to explain variation in the transcription of KCNQ1 and other genes that may act to modify the clinical expression of LQTS. The goals of this study are consistent with the mission of NHLBI. Relevance to Public Health - Identification of long QT syndrome (LQTS) modifiers will enhance our understanding of the pathophysiology of an inherited cause of sudden cardiac death (SCO), provide valuable new information to promote more accurate risk counseling for LQTS families, and will contribute to our understanding of more common arrhythmia syndromes associated with highly prevalent cardiac diseases (e.g. ischemic heart disease and congestive heart failure) that are burdened by a high incidence of SCO.